Kaposi's sarcoma-associated virus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The KSHV genome encodes a protein named K1 that has been shown to activate B cell signaling pathways and transform cells. The K1 gene is encoded by the first open reading frame of KSHV and is in an equivalent genomic position as HVS STP and RRV R1. The proposed study is directed towards understanding the functional role of the KSHV K1 protein. We will investigate the molecular mechanism of deregulation of cell growth control induced by the KSHV K1 protein. We have previously shown that K1 can upregulate angiogenic factors and protect cells from Fas-mediated apoptosis. Our hypothesis is that the signaling function of K1 plays a significant role in KSHV-associated pathogenesis through a paracrine mechanism. We propose to characterize the mechanism of K1 signaling and determine how it protects cells from apoptosis. We will also investigate how K1 signaling is regulated at the molecular level. Additionally, signaling by K1 may be needed to activate the cell and enhance viral replication. Hence we will also investigate the role of K1 in viral lytic replication. Thus, we propose to analyze the detailed biochemical mechanisms of K1 function, as well as to assess the biological role of K1 in the lifecycle of the virus. The proposed studies will provide significant and biologically relevant insights into the functions of this viral gene. [unreadable] [unreadable] [unreadable]